Cellular mechanisms underlying short-term memory in the hippocampal CA1 region

短期记忆是一种认知功能，它使我们能够在大脑中短时间(长达数十秒)地记住信息。它在日常生活中是理解言语、做出决定、解决问题和执行许多其他认知功能所必需的。因此，了解短期记忆的细胞机制和分子相关性对于维持或改善神经退行性疾病的生活质量以及在短期记忆功能下降的自然衰老过程中具有重要意义。经典地认为，突触网络支持的神经元的持续放电活动(持续放电)将信息保持为短期记忆。相反，我们和其他人已经确定了瞬时受体电位规范(TRPC)通道参与单个神经元的持续放电，而不依赖于突触网络。然而，这些研究仅限于体外实验，多年来仍不清楚TRPC通道是否支持体内持续放电和短期记忆表现。然而，最近，我们等人在小鼠身上证明了TRPC通道在短期记忆和体内神经活动中的作用，表明TRPC通道可能是短期记忆的关键机制。在这个项目中，我们通过解决当前的争议和扩大我们对TRPC通道在活体海马区中的作用的理解，进一步阐明了TRPC通道的具体作用。首先，在TRPC基因敲除小鼠中观察到的完整持续放电挑战了TRPC通道在单个神经元持续放电中的作用。我们的目标是通过在体外结合遗传和药物操作来解决这个问题。其次，TRPC通道在体内神经活动中的作用在很大程度上仍不清楚。因此，我们将进行体内电生理记录，以研究TRPC通道操作对持续放电和其他记忆相关活动的影响。这些实验将对持续放电和短期记忆的核心机制，以及由于衰老或病理造成的认知缺陷提供深入的见解。

Short-term memory is a cognitive function which enables us to mentally retain information for short periods of time (up to tens of seconds). It is required in daily life in order to understand speech, make decisions, solve problems, and perform many other cognitive functions. Understanding cellular mechanisms and molecular correlates of short-term memory is, therefore, of great importance for maintaining or improving quality of life in neurodegenerative disorders, as well as during natural aging processes in which short-term memory function declines. Classically, it has been believed that sustained spiking activity of neurons (persistent firing) supported by synaptic network maintains information as short-term memory. In contrast, we, and others, have established the involvement of transient receptor potential canonical (TRPC) channels in persistent firing in individual neurons, independent of the synaptic network. However, these studies were limited to in vitro experiments, and for many years it remained unclear whether TRPC channels could support in vivo persistent firing and short term memory performance. More recently, however, the role of TRPC channels in short-term memory and in vivo neural activity has been demonstrated by us, among others, in mice, indicating that TRPC channels may be a key mechanism of short-term memory. In this project, we further clarify the specific role of TRPC channels by resolving the current controversy and by extending our understanding of the role of TRPC channels in vivo in the hippocampus. First, the observation of intact persistent firing in TRPC knock-out mice challenges the role of TRPC channels in persistent firing in individual neurons. We aim to resolve this issue by combining genetic and pharmacological manipulations in vitro. Second, the roles of TRPC channels in neural activity in vivo still remain largely unknown. Therefore, we will conduct in vivo electrophysiological recordings in order to investigate the effect of TRPC channel manipulations on persistent firing and other memory related activity. These experiments will provide insights into the core mechanism of persistent firing and short-term memory, and into cognitive deficits due to aging or pathology.